Obesity has become a serious health problem in the United States. Once obesity is established there is little effective treatment. It is increasingly apparent that in addition to excess food intake, energy expenditure is an important contributor to the development of obesity, both in rodents and humans. Energy expenditure has several components including resting energy expenditure and the energy spent during locomotor activity (motivated behavior). It is now recognized that peptides that play are role in feeding also regulate energy expenditure. Thus peptides that increase appetite then to decrease energy expenditure while those that inhibit appetite tend to increase energy expenditure. Melanin-concentrating hormone (MCH) was initially identified as a neuropeptide that stimulates appetite. It has also emerged as a key regulator of energy expenditure and has effects both on resting energy expenditure, probably through modulation of sympathetic activity, as well as energy expenditure associated with locomotor activity, most likely through influences on dopaminergic signaling. We have developed a mouse model lacking the gene for MCH (MCH-KO or MCH-/-) and backcrossed the animals for 10 generations onto a homogeneous genetic background, C57BL/6. Mice lacking MCH are lean. On a mixed background leanness resulted from a combination of decreased feeding and increased energy expenditure. On the BL/6 background the lean phenotype is secondary to increased energy expenditure. On a chow diet, resting energy expenditure is increased and there is no change in locomotor activity. Mice lacking MCH resist diet induced obesity; when placed on a HF diet MCH-KO demonstrate and additional increase in resting energy expenditure as well as increased locomotor activity. The aims of this grant are to use this mouse model which lacks MCH to examine the role of MCH in modulate sympathetic activity and dopaminergic signaling.